A novel enantioselective (up to 90% ee) Michael addition of a-substituted cyanoacetates to a,b-unsaturated selenones in the presence of bifunctional urea and thiourea organocatalysts is described. The Michael adducts, containing an allcarbon quaternary stereocenter, are smoothly converted into synthetically useful polyfunctional compounds by taking advantage of the excellent leaving group ability of the selenone group.Keywords: asymmetric organocatalysis; cyanoacetates; Michael addition; selenones; thiourea catalysts In recent years asymmetric organocatalysis has emerged as a practical and powerful tool for the stereoselective preparation of chiral molecules with an impressive number of synthetic applications, also in the field of natural or biologically active compounds. [1,2] Fundamental carbon-carbon bond forming processes, such as the Michael reaction, have been widely investigated. Various catalysts, activating the nucleophile or the electrophile by formation of covalent bonds or weaker interactions, such as ion pairing or hydrogen bonding, have found application for this versatile transformation. [1,2] Among them, the socalled bifunctional catalysts, [2] bearing an hydrogenbond donor group besides a basic site on a chiral scaffold, have received great attention for the enantioselective addition of 1,3-dicarbonyl compounds or their equivalents to electron-deficient alkenes. [1,2] The simultaneous activation of both the nucleophile and the electrophile allows an excellent level of stereocontrol over the addition event. To date nitroalkenes [3] and a,b-unsaturated carbonyl compounds, [4] imides, [5] nitriles [6] or sulfones [7] have been employed as Michael acceptors. The discovery of novel substrate combinations should provide a simple and convenient access to highly functionalized adducts. Our interest in the field of the organoselenium-based asymmetric syntheses [8] prompted us to investigate the addition of carbon-centered nucleophiles to vinyl selenones. Selenones are well recognized intermediates in organic synthesis with peculiar properties in respect to the sulfur analogues. Thus, for instance, the selenonyl group presents an exceptional aptitude to act as a leaving group.[8b-e,9] Herein, we report the first enantioselective addition of a-substituted cyanoacetates to vinyl selenones. The use of these trisubstituted Michael donors in asymmetric conjugate addition represents one of the most attractive solutions to the challenging problem of generating selectively all-carbon quaternary stereocenters. [10] First experiments were effected on the a-phenyl cyanoacetate 2a and the vinyl selenone 3 in toluene. [11] The easily accessible bifunctional catalysts 1a-f reported in Figure 1, containing phenolic (1a), ureidic (1b, 1d and 1e) or thioureidic (1c and 1f) hydrogen donor groups, respectively, have been examined as catalysts. Cinchonine, quinine and the commercially available Cinchona alkaloid derivatives (DHQ) 2 Pyr and (DHQ) 2 AQN, that lack an H-bond donor group, have also been tested for compa...
A novel organocatalytic method for the stereoselective synthesis of highly substituted cyclopropanes is reported. The Michael adducts, generated through the addition of a-substituted cyanoacetates to easily accessible vinyl selenones catalyzed by a bifunctional ureidic catalyst, smoothly cyclize by intramolecular alkylation induced by a de-eth-A C H T U N G T R E N N U N G oxycarbonylation process. The one-pot sequence generates cyclopropanes bearing adjacent tertiary and quaternary stereocentres as single Z-isomers in moderate to high yields and good enantiomeric excesses.Keywords: asymmetric organocatalysis; cyclopropanes; Michael addition; quaternary stereocenters; selenones The cyclopropane ring is the basic structural motif of a wide range of natural products and biologically active compounds, such as conformationally restricted amino acids or peptides, enzyme inhibitors and therapeutic agents with antipsychotic, antifungal, antibacterial, antitumoral or antiviral activities.[1] Furthermore, the three-membered ring, due to its strong angular strain and great ring-opening ability, is a recognized intermediate in the construction of complex molecular skeletons.[2] On these grounds, the development of simple and efficient methods for the stereocontrolled preparation of variously substituted cyclopropanes remains an interesting task for synthetic chemists. In the last years great attention has been focused on the identification of new asymmetric methodologies based on readily available achiral starting materials and chiral catalysts. Thus, asymmetric SimmonsSmith reactions or cyclopropanations of olefins by metal-catalyzed decomposition of diazo compounds have been successfully explored.[3] Very recently significant advances have also been made in the development of organocatalytic cyclopropanations based on Michael initiated ring closure reactions (MIRC). [3,4] In these processes, the addition of an ylide or an enolate containing a good leaving group to an electrophilic alkene generates an anionic intermediate, which easily undergoes a ring closure reaction by intramolecular alkylation. During our studies on the asymmetric Michael addition of a-substituted cyanoacetates to vinyl selenones catalyzed by ureidic or thioureidic bifunctional catalysts, we observed that the diastereomeric mixture of Michael adducts 4aA and 5aA affords the cyclopropane 6aA as a single isomer by simple treatment with KCN in DMF (Scheme 1). [5] We explained this process as a Krapcho-type deethoxycarbonylation, followed by an intramolecular nucleophilic substitution of the selenonyl moiety by the enolate intermediate. The excellent leaving group properties of this species have been already exploited for other synthetically useful inter-or intramolecular substitutions. [5,6] This first result prompted us to study the sequence in detail and develop a novel one-pot Scheme 1. Formation of the cyclopropane 6aA.
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